WO2002068407A1 - Compose benzimidazole - Google Patents

Compose benzimidazole Download PDF

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Publication number
WO2002068407A1
WO2002068407A1 PCT/JP2002/001741 JP0201741W WO02068407A1 WO 2002068407 A1 WO2002068407 A1 WO 2002068407A1 JP 0201741 W JP0201741 W JP 0201741W WO 02068407 A1 WO02068407 A1 WO 02068407A1
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Prior art keywords
group
alkyl
substituted
compound
bond
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PCT/JP2002/001741
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English (en)
Japanese (ja)
Inventor
Kazuhisa Takayama
Takenori Kimura
Naoyuki Masuda
Ryo Naito
Yoshinori Okamoto
Yuji Koga
Yohei Okada
Makoto Takeuchi
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Yamanouchi Pharmaceutical Co., Ltd.
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Priority to JP2002567921A priority Critical patent/JPWO2002068407A1/ja
Publication of WO2002068407A1 publication Critical patent/WO2002068407A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to medicaments, particularly to benzimidazole derivatives useful as PARP inhibitors.
  • Rheumatoid arthritis (rheumatoid arthritis: RA) is a polyarthritis that recurs and remits repeatedly, causing joint destruction, with extra-articular manifestations, and sometimes a life-threatening disease. Characteristics of RA include (1) infiltration of monocytes, (2) proliferation of synovial cells, and (3) consequent tissue rupture (N. Engl. J. Med., 322, 1277). -1289 (1990)). Therefore, the purpose of pharmacotherapy is to maintain joint function and prevent bone fractures observed by X-rays.
  • PARP Poly (ADP-ribose) polymerase
  • PARP Poly (ADP-ribose) polymerase
  • the motif recognizes DNA strand damage and places nicotinamide adenine dinucleotide (nicotinamide adenine dinucleotide) on various nuclear proteins, including histones and DNA topoisomerases I and II. It is known to control the polymerization of the ADP-ribose moiety of dinucleotide (NAD). Therefore, it is thought that excessive activation of PARP depletes intracellular NAD and ATP contents and leads to cell death (J. Clin. Invest, 77, 1312-1330 (1986)).
  • synovial fluid cells have an increased ability to produce active oxygen (Z. Rheumatol., 46, 227-232 (1987)), and the amount of NCV ions in synovial fluid and serum is markedly increased.
  • Am. Rheum. Dis., 51, 1219-1222 (1992) increased DNA strand damage in peripheral mononuclear cells (Aim. Rheum. Dis, 51, 8-12 (1992))
  • NAD content was reduced
  • PARP inhibitors are considered to be useful as therapeutic agents for inflammatory diseases such as RA.
  • inflammatory diseases such as RA.
  • no clinically effective PARP inhibitor has been found, and the development of a novel PARP inhibitor having excellent inhibitory activity is eagerly desired.
  • WO 00/32579 discloses a PAR inhibitor having an unsubstituted carpamoyl group at the 4-position of a benzimidazole and a nitrogen-containing saturated heterocycle at the 2-position, as shown in the following formula.
  • A represents a 4- to 8-membered saturated or monoethenoid heterocycle having substituents R 2 and R 3 and containing one or two N atoms.
  • R 2 is H ;
  • NR 26 R 27 or Okiso may be substituted with a group branched or linear C I-8 alkyl; C 3-7 Shikuroarukinore - C M alkyl le; CO-CNH ⁇ -R 21; C0 2 R 21 ; or an optionally substituted phenol (R 21 represents C 3-7 cycloalkyl or phenyl, etc.);
  • R 3 is H; even if it is substituted with a phenyl group, A good branched or straight-chain C 1-8 alkyl, etc.
  • NR 26 R 27 in R 2 may form a 3- to 8-membered hetero ring, and the hetero ring is C w It may be substituted by alkyl or C 1-4 alkyl-phenyl.
  • the ehich compound has a nitrogen-containing saturated hetero ring at the 2-position, and the hetero ring can be further bonded to another ring via a bond.
  • the bond is an oxo group. it may also be substituted Rere C 1-8 alkylene, CO-iNH) (u, C0 2 or a bond.
  • the ring is (1) a C 1-8 alkylene which may be substituted with an oxo group, a 3- to 8-membered nitrogen-containing hetero ring bonded with N, (2) a C 1-4 alkylene, CO- CNH; ⁇ or in the case of C0 2, full Eniru or C 3-7 cycloalkyl, (3) C 5-8 when alkylene or a bond, are limited respectively phenyl, and. Disclosure of the invention
  • the present inventors have conducted intensive studies on compounds that inhibit PARP.As a result, the benzimidazole has an unsubstituted rubamoyl group at the 4-position and a nitrogen-containing saturated hetero ring at the 2-position.
  • a benzimidazole derivative in which one or more ring groups are further bonded to a terrorist ring via a specific bond has been found to have good PARP inhibitory activity, especially when administered orally. Furthermore, they have found that they are useful as agents for preventing, treating or diagnosing diseases involving PARP, and completed the present invention.
  • a benzimidazole derivative represented by the following general formula (I) (hereinafter, referred to as “the compound (I)” of the present invention) or a pharmaceutically acceptable salt thereof,
  • a drug particularly a PARP inhibitor, containing one or more species as active ingredients.
  • R 1 H, lower alkyl, halogen, or a lower alkyl group substituted with halogen
  • R 2a and R 2b H, lower alkyl or absent
  • Dotted line presence or absence of a double bond in the ring
  • Y 1 and Y 3 the same or different, and a lower alkylene optionally substituted with an oxo group, a lower alkenylene optionally substituted with an oxo group, a lower alkynylene optionally substituted with an oxo group, or Join, Y 2: 0, S, SO , S0 2 or a bond (when ⁇ and Y 1 is methylene or a bond, Upsilon 2 is shows the binding),
  • ⁇ cycloalkyl which may be substituted, aryl which may be substituted or heterocyclic group which may be substituted (provided that the heterocyclic group is bonded via a carbon atom which is a ring atom. 3 ),
  • the dotted line in the formula (I) indicates that the benzimidazole ring has one of the following structures in combination with R 2a and R 2b .
  • alkyl alkylene
  • alkenylene alkynylene
  • lower alkyl is, for example, an alkyl group of C Les 6, preferably an alkyl group of C 1-4, more preferably methyl, Echiru and Isopuropiru group.
  • Lower alkylene is, for example, c 1-6 alkylene, preferably c 2-4 alkylene, and more preferably ethylene and butylene.
  • “Lower alkenylene” means having one or more double bonds at any position of, for example, C 2-6 alkyl
  • “lower alkynylene” means, for example, any of the C 2-6 alkyl chain. It means having one or more triple bonds at the position.
  • Halogen refers to F, Cl, Br and I, preferably F, C1 and Br.
  • the term "lower alkyl substituted with halogen” means, for example, C 1-6 alkyl substituted with one or more halogen, preferably C 1-6 alkyl substituted with one or more F. Yes-more preferred are fluoromethyl, difluoromethyl, trifluoromethyl and trifluoroethyl.
  • the “cycloalkyl group” is preferably a cycloalkyl group having 3 to 14 carbon atoms, and may be crosslinked. More preferred are pentyl, neck hexyl, neck heptyl and adamantyl groups.
  • the “aryl group” is preferably a monocyclic to tricyclic aryl group having 6 to 14 carbon atoms. More preferred are phenyl and naphthyl groups, and still more preferred are phenyl groups. Further, a 5- to 8-membered cycloalkyl ring may be condensed to the phenyl group to form, for example, an indanyl or tetrahydronaphthyl group.
  • heterocyclic group refers to a 5- to 8-membered monocyclic to tricyclic heterocyclic group containing 1 to 4 heteroatoms selected from 0, S and N as ring atoms. Any carbon atom that is a ring atom may be substituted with an oxo group, and S or N may be oxidized to form an oxoxide dioxide.
  • the heterocyclic group may be cross-linked or may form a spiro ring (including an acetal derivative such as a 1,3-dioxolane ring derived from an oxo group). Also, a cycloalkyl ring or a benzene ring may be condensed.
  • “Nitrogen-containing saturated heterocyclic group” has at least one N as a ring atom, Further, it is a 5- to 8-membered saturated heterocyclic group which may have one O or S, and any carbon atom which is a ring atom may be substituted with an oxo group, and S or N is oxidized.
  • the oxide may form a dioxide.
  • the heterocyclic group may be cross-linked or may form a spiro ring (including an acetal derivative such as a 1,3-dioxolane ring derived from an oxo group).
  • Heterocyclic group bonded to Y 3 via a carbon atom that is a ring atom refers to a group represented by an adjacent linker represented by —YLY ⁇ Y 3 — (for example, when Y 2 and Y 3 are both In the case of a bond, it represents a heterocyclic group in which the ring atom bonded to Y 1 ) is a carbon atom. For example, it does not include 1-piperidyl, but does include 2-, 3- or 4-piperidyl.
  • substituents in the “optionally substituted cycloalkyl”, the “optionally substituted aryl” or the “optionally substituted heterocyclic group” include those rings in a drug, particularly a PARP inhibitor. Is a substituent that can be used as a substituent of the above, and may have 1 to 5 of these substituents.
  • the hydrocarbon group and the heterocyclic group may further have a substituent, and the substituent is preferably C 1-6 alkyl, halogen, OH, 0—C 1-6 alkynole, SH, S—.
  • R 1 is H, R 2a or R 2b is H, X is a bond or C 1-6 alkylene, A is pyrrolidinyl or piperidyl, Y 1 is C 1-6 alkylene, Y 2 is 0, S or a bond, Y 3 is a C 1-6 alkylene or a bond, Z is an optionally substituted cycloalkyl, an optionally substituted aryl or a substituted heterocyclic compound. . More preferably, it is a compound of an optionally substituted cycloalkyl, an optionally substituted phenyl or an optionally substituted heterocyclic group, and further preferably, X and Y 3 are a bond.
  • a compound in which ⁇ 2 is 0 or 8, and Z is optionally substituted and (2) a compound in which Y 2 is bonded and Z is substituted It is a compound of a good aromatic heterocyclic group.
  • Group G 2-phenoxyshetinole, 3-phenoxypropyl, 4-phenoxybutyl, 6-phenoxyhexyl, 2- (2-fluorophenoxy) ethyl, 3- (2-phenolelophenol) B) propyl, 4- (2-fluorophenoxy) butyl, 2- (3-fluorophenoxy) ethyl,
  • particularly preferred compounds are 2- [1- (6-phenoxyhexyl) piperidin-4-yl] -1H-benzimidazole-4-carboxamide, 2- ⁇ 1- [ 2- (4-Fluorophenoxy) ethyl] piperidin-4-yl ⁇ -1 ⁇ ⁇ ⁇ -benzoimidazo-mono--4-propanolamide, 2- ⁇ 1- [4- (4-funolelophenoxy) butyl] pi ⁇ Lysin-4-yl ⁇ -1 ⁇ -benzimidazonole-4-carboxamide, 2- ⁇ 1- [3- (3-phenyl-1,2,4-oxaziazol-5-yl) propyl] Piperidine-4-ino-W-1H-benzimidazole-4-carboxamide and 2- ⁇ 1- [2- (2-phenyl-oxazole-4-yl) ethyl] piperidine-4-inole ⁇ - 111
  • the compound (I) of the present invention may have a geometrical isomer or a tautomer depending on the kind of the substituent, and the present invention also includes a separated form or a mixture of these isomers.
  • the compound (I) of the present invention may have an asymmetric carbon atom, and may have an isomer based on the asymmetric carbon atom.
  • the present invention includes a mixture of these 14 optical isomers and isolated ones.
  • the present invention also includes a compound obtained by labeling the compound (I) of the present invention with a radioisotope.
  • the compound (I) of the present invention may form an acid addition salt or a salt with a base depending on the type of the substituent, and is included in the present invention as long as the strong salt is a pharmaceutically acceptable salt.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, and maleene Acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, glutamic acid and other organic acids and acid addition salts, sodium, potassium, magnesium, calcium, aluminum and other inorganic acids Bases, salts with organic bases such as methylamine, ethynoleamine, ethanolanolamine, lysine, and onolenitine, and ammonium salts, and
  • the compounds of the present invention also include pharmacologically acceptable prodrugs.
  • a pharmacologically acceptable prodrug is a conjugate having a group that is converted to NH 2 , OH, CO 2 H or the like of the present invention by solvolysis or under physiological conditions.
  • Prodrug-forming groups include those described in Prog. Med., 5, 2157-2161 (1985) and “Development of Drugs” (Hirokawa Shoten, 1990), Vol. 7, Molecular Design 163-198. Can be
  • the compound (I) of the present invention and a pharmaceutically acceptable salt thereof can be produced by applying various known synthetic methods, utilizing characteristics based on the basic skeleton or the type of the substituent. Can be. At that time, depending on the type of the functional group, it is necessary to protect the functional group with an appropriate protecting group at the stage of raw materials or intermediates, or to replace it with a group that can be easily transferred to the functional group. May be effective.
  • Such functional groups include, for example, amino groups, hydroxyl groups, carboxyl groups, and the like, and their protecting groups include, for example, "Protective Groups in Organic Synthesis (Third Edition, TW Greene) and PGM Wuts (Third Edition, 1999)], and these may be appropriately selected and used depending on the reaction conditions.
  • the desired compound can be obtained by introducing the protective group and performing a reaction, and then removing the protective group or converting it to a desired group, if necessary.
  • the prodrug of the compound (I) of the present invention can be produced by introducing a specific group at the stage of a raw material or an intermediate, or performing a reaction using the obtained compound (I) of the present invention, similarly to the above-mentioned protective group.
  • the reaction can be carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation, dehydration and the like.
  • the compound ( ⁇ ) of the present invention in which one of R 2a or R 2b is H can be produced according to the following route.
  • R A is CONH 2, or readily Utati ⁇ groups to CONH 2 (C0 2 H, the carboxylic acid ester or CN, etc.)
  • L is a leaving group
  • P 1 is H or C 1 -6 coercive of C0 2 H and alkyl groups
  • P 2 represents a protecting group for H or an amino group
  • a ′ represents a group having a ring atom N at the position where A is bonded to Y 1 . The same applies hereinafter.
  • the present production method is a method for obtaining the compound (I ′) of the present invention by subjecting the starting compound ( ⁇ ) to an alkylation reaction.
  • the leaving group represented by L include halogen atoms such as Cl, Br, and I; alkylsulfonyloxy groups such as methanesulfonyloxy group and ethanesulfonyloxy group; benzenesnolephoninoleoxy group; and toluene (particularly, P-toluene).
  • Examples include organic sulfonic acid residues such as arylsulfonyloxy groups such as sulfonyloxy groups.
  • Reactions include aromatic hydrocarbons such as benzene and toluene, ethers such as dimethyl ether, tetrahydrofuran (THF), and dioxane; halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform; methanol, ethanol, and the like.
  • aromatic hydrocarbons such as benzene and toluene
  • ethers such as dimethyl ether, tetrahydrofuran (THF), and dioxane
  • halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform
  • methanol, ethanol, and the like methanol, ethanol, and the like.
  • ⁇ , ⁇ -dimethylformamide (DMF), dimethylsulfoxide (DMSO), etc. equimolar amounts of compound ( ⁇ ) and compound (III) or an excess amount of one of them is used.
  • the reaction is performed under cooling at a temperature of 178 ° C to 0 ° C, under cooling to room temperature, at room temperature, or in some cases at room temperature to heating.
  • sodium hydride, potassium hydride, lithium disopyl pyramide, lithium hexamethyldisilazide, sodium methoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, carbon dioxide It is preferable to carry out the reaction in the presence of a base such as lime.
  • the compound (III) of the present invention can also be produced by a reductive alkylidation reaction.
  • the starting compound ( ⁇ ) instead of the starting compound ( ⁇ ), the corresponding carbonyl disulfide is used, and the conventional method of reductive alkylation is used (for example, “The Experimental Chemistry Course (Maruzen)” edited by The Chemical Society of Japan (4th edition) , Vol. 20, 1992, 300)).
  • R a starting compound (II) is other than CONH 2
  • at the stage of the raw material I ⁇ product ([pi), or after ⁇ alkylation reaction can be converted to the desired CON3 ⁇ 4 group.
  • R a is C0 2 H, halogenation hydrocarbons, aromatic hydrocarbons, ethers, DMF, DMSO, in a solvent inert to the reaction such as pyridine, a condensing agent (e.g., hexyl Cal positive imide dicyclohexyl (DCC), diisopropylpropylcarbodiimide (DIPC) ⁇ 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC), ⁇ , ⁇ -carbonylbis-1H-imidazole (CDI), etc.
  • a condensing agent e.g., hexyl Cal positive imide dicyclohexyl (DCC), diisopropylpropylcarbod
  • Ra is a carboxylic acid ester
  • it can be produced by reacting with ammonia in a solvent inert to a reaction such as water, alcohols, DMF, THF or the like, or at room temperature or under heating, and optionally under pressure, in a solvent without solvent.
  • a reaction such as water, alcohols, DMF, THF or the like, or at room temperature or under heating, and optionally under pressure, in a solvent without solvent.
  • Ra is CN, it can be produced directly to the CON group by hydrolysis or via CO 2 H.
  • the starting compounds (IV) and (VII) are subjected to an amidation reaction to obtain an intermediate (VIII), and the obtained compound (VIII) is subjected to a cyclization reaction to obtain the present compound ( ⁇ ) Is the way.
  • the compound of the present invention (III) can also be obtained without isolating the intermediate (VIII) and subjecting it to the cyclization reaction conditions after the amidation reaction.
  • the reaction is carried out in a solvent inert to the reaction, such as aromatic hydrocarbons, ethers, halogenated hydrocarbons, DMF, DMSO, etc., a condensing agent such as DCC, DIPC, WSC, CDI, etc., and optionally HONSu, HOBt Compound (IV) and Compound (VII) are used in an equimolar amount or an excess amount in the presence of an additive, etc., under cooling at 178 ° C to 0 ° C, under cooling to room temperature, The reaction is performed at room temperature or, in some cases, at room temperature or under heating.
  • a solvent inert such as aromatic hydrocarbons, ethers, halogenated hydrocarbons, DMF, DMSO, etc., a condensing agent such as DCC, DIPC, WSC, CDI, etc., and optionally HONSu, HOBt Compound (IV) and Compound (VII) are used in an equimolar amount or an excess
  • various reactive derivatives may be used in place of the starting compound (VII).
  • the reactive derivative include: acid anhydrides; ordinary esters such as carboxylic acid methyl ester and ethyl ester; acid chlorides, acid halides of acid promide; acid azides; phenolic compounds such as P-ditrophenol, HONSu, HOBt and the like.
  • Ester obtained by reacting with N-hydroxyl compound of organic acid organic acid-based mixed acid anhydride or salt obtained by reacting with halocarbonic acid alkyl ester such as alkyl carbonate halide or Viva ethyl halide;
  • a mixed acid anhydride such as a phosphoric acid mixed acid anhydride obtained by reacting phosphoryl can be used.
  • the reaction is carried out in an organic solvent inert to the reaction of aromatic hydrocarbons, halogenated hydrocarbons, ethers, etc., or in the absence of a solvent, using a catalytic amount or a solvent amount of acid, at a temperature of 78 ° C to 0 ° C
  • the reaction is carried out under cooling, under cooling to room temperature, at room temperature, or in some cases at room temperature to heating.
  • the acid used include acetic acid, sulfuric acid, hydrochloric acid, phosphoric acid, methanesulfonic acid, P-toluenesulfonic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid.
  • Compound (II) can be produced from compound (IV) and (V) by subjecting it to the same conditions as in the above amidation and cyclization reaction.
  • Compound (VII) can be produced from compounds (IX) and (III) under the same conditions as in the above alkylidation reaction.
  • Compound (IV) can be produced by the method described in US5380719 and the like. Many compounds such as isisonipecotic acid are commercially available as compounds (V) and (IX), or readily available compounds can be easily produced by applying a known reaction.
  • the compound ( ⁇ ) in which X is C 1-6 alkylene in (IX) can also be produced by the following method. Reduction P 1 OOC R B
  • R b is -A'-P 2 or C 1-4 alkylene-A'-P 2
  • R c is H or C 1-4 alkyl, or a carbon atom to which R b and R e are bonded. Together, they represent -A'-P 2.
  • R d represents a group generally usable for the reaction, such as a C 1-4 alkyl group.
  • TosMIC tosylmethyl isocyanide
  • Compound (III) can be easily prepared from commercially available compounds or commercially available compounds.
  • the leaving group for L can be easily produced from an OH group or a CO 2 H group by an ordinary method.
  • Y 2 is 0 or compounds S are Eterui ⁇ by esterification reaction, the compound Y 2 is SO or S0 2 can be easily produced respectively by Sani spoon the S.
  • Compounds having various substituents on the ring group Z can be easily produced by a known method.
  • a 1,2,4-oxadiazole derivative is an N-hydroxyamidine derivative
  • Oxazole derivatives react with 2-haloketone derivatives and amide derivatives by condensation of oxazoles with carboxylic acid derivatives such as acid oxalates (J. Med. Chem. 29, 2174-2183 (1986)). Chem. 39, 237-245 (1996)), isoxazole derivatives can be condensed with 1,3-diketone derivatives and hydroxylamine (J. Med. Chem. 31, 1659-1664 (1988)) or nitritoloxide.
  • Thiazole derivatives can be converted to 2-haloketone derivatives and thioamide derivatives (Gazz.
  • the compound of the present invention wherein one of R 2a or R 2b is lower alkyl is produced by subjecting the above intermediate (IV), (VI) or (VIII) or the compound of the present invention ( ⁇ ) to an alkylidation reaction. it can.
  • the reaction conditions the same conditions as in the above-described alkyl can be applied.
  • the compound of the present invention has a substantially similar manner to the above-mentioned production method even when the ring is other than A ′, It can be produced by a method obvious to those skilled in the art.
  • the reaction product obtained by each of the above production methods can be isolated and purified as various solvates such as a free compound, a salt thereof, or a hydrate.
  • the salt can be produced by subjecting the salt to a usual salt formation treatment.
  • Isolation and purification can be performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography.
  • optical isomers can be isolated by a conventional method utilizing physical differences between the isomers.
  • the optical isomers can be separated by a general optical resolution method, for example, fractional crystallization or chromatography.
  • the optical isomer can also be produced from a suitable optically active raw material mixture.
  • the compounds of the present invention are useful as active ingredients in pharmaceutical preparations.
  • it has PARP inhibitory activity, and therefore, PARP-related inflammatory diseases (eg, rheumatoid arthritis, ulcerative colitis, Crohn's disease, peritonitis, pleurisy, nephritis, etc.), autoimmune diseases (eg, type I diabetes) Etc.), Prevention of diseases associated with ischemia reperfusion disorder (eg, stroke, myocardial infarction, organ transplantation, etc.) ⁇ It is useful as a therapeutic drug.
  • PARP-related inflammatory diseases eg, rheumatoid arthritis, ulcerative colitis, Crohn's disease, peritonitis, pleurisy, nephritis, etc.
  • autoimmune diseases eg, type I diabetes
  • ischemia reperfusion disorder eg, stroke, myocardial infarction, organ transplantation, etc.
  • Test compound desired concentration 82.5 mM Tris -HC1 (pH 8.0), 50 mM chloride force Riu arm, 10 mM magnesium chloride, 5 mM dithiothreitol I torr, 100 g / ml histone, 26 nM 3 H-
  • the reaction was carried out at 25 ° C for 3 hours in a reaction solution containing NAD and 0.06 unit human recombinant PARP.
  • IC 50 was calculated for each compound as the concentration of the test compound that inhibited the ADP-ribose polymerization activity of PARP by 50%.
  • J774.1 cells (murine monocyte / macrophage cell line) was adjusted to 5 X 10 5 cells / ml in 25 mM HEPES and 10% fetal bovine serum-containing DMEM medium, of 37 ° C, 5% C0 2 The cells were cultured under the conditions for 24 hours.
  • IC 50 was calculated for each compound as the concentration of the test compound that inhibited the ADP-ribose polymerization activity of PARP by 50%.
  • Example 1 6 2, 7 2, 7 7 A compound according to ⁇ Pi 8 8, respectively 8.2, 47, 5.1, showed 10 ⁇ Pi 6.1 nM of IC 50.
  • mice Male and female Balb / c mice (Nippon-charlsriver) were used for the experiment.
  • mice were fasted and had free access to water from the evening before the test.
  • test compound suspension was orally administered to the above-mentioned Balb mouse at 5 ml / kg to a desired dose.
  • a solvent, 0.5% methyl senorellose was administered at 5 ml / kg.
  • Zymosan (Sigma) was suspended in physiological saline to a concentration of 0.5 mg / ml, and the compound was orally administered and intraperitoneally at 1 ml / mouse. To the negative control group, physiological saline was intraperitoneally administered at 1 ml / mouse.
  • ED30 is a test compound that inhibits the number of cells infiltrated into the abdominal cavity by 30% by Zymosan The dose was calculated for each compound.
  • the booster day was set as day 0, and the body weight and arthritis score of each body were measured twice a week.
  • the arthritis score was set as follows. 0 is normal, 1 is redness and mild swelling, 2 is moderate swelling, 3 is severe swelling or joint stiffness.
  • Test compounds were suspended at concentrations of 1, 3, 10, and 30 mg / 5 ml in 0.5% methylcellulose as a solvent, and were orally administered once daily at a dose of 5 ml / kg until day 21. .
  • 0.5% methylcellulose as a solvent was administered at 5 ml / kg.
  • the compound of the present invention has a PARP inhibitory activity and is useful as a prophylactic / therapeutic agent for diseases involving PARP.
  • compositions containing one or more of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient can be used as a pharmaceutical carrier, excipient and a carrier commonly used in the art.
  • the compound can be prepared by a commonly used method using an agent.
  • the solid composition for oral administration tablets, powders, granules and the like are used.
  • one or more active ingredients may be combined with at least one inert excipient such as lactose, mannitol, pudose, hydroxy It is mixed with cypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminate metasilicate and the like.
  • the composition may contain an inactive additive such as a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, and a solubilizing agent according to a conventional method.
  • Tablets or pills may be coated with sugar coating or a gastric or enteric coating, if necessary.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert solvents such as purified water, ethanol and the like. including.
  • the composition may contain, in addition to the inert solvent, auxiliaries such as solubilizing agents, wetting agents, and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • Aqueous solvents include, for example, distilled water for injection and physiological saline.
  • the non-aqueous solvent include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysonolate 80 (trade name).
  • Such compositions may further include a tonicity agent, a preservative, a wetting agent, an emulsifier, a dispersant, a stabilizer, and a solubilizing agent. These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. In addition, these can be used by preparing a sterile solid composition, dissolving and suspending in sterile water or a sterile injection solvent before use.
  • Transmucosal preparations such as nasal preparations are used in solid, liquid or semi-solid form, and can be produced according to conventionally known methods.
  • known pH adjusters, preservatives, thickeners and excipients are appropriately added, and the mixture is shaped into a solid, liquid or semi-solid.
  • Nasal drugs are administered using ordinary spraying equipment, nasal drops, tubes, nasal implants and the like.
  • the daily dose is about 0.001 to 100 mg / kg, preferably 0.1 to 10 mg / kg per body weight, which is divided into single doses or 2 to 4 doses.
  • the daily dose is suitably from about 0.0001 per weight 10 mg / kg, is administered in once to several times a day.
  • the appropriate daily dose is about 0.0001 to 10 mg / kg per body weight.
  • the dose is administered once to several times a day.
  • a transmucosal agent about 0.001 to 100 1100 / 13 ⁇ 4 per body weight is administered once a day or divided into multiple doses. The dose is determined as appropriate for each individual case, taking into account symptoms, age, gender, etc.
  • BEST MODE FOR CARRYING OUT THE c invention as
  • CDI (16.2 g) was added to a suspension of 2- (l-tert-butoxycarbonylpyridine-4-inole) -1H-benzoimidazole-4-carbonic acid (23.2 g) in THF (300 ml). Was added and stirred at room temperature for 3 hours. Ammonia saturated THF (200 ml) was added to the reaction solution, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate.
  • Trifluoroacetic acid 50 ml was added to 2- (l-tert-butoxycarbonylpyridine-4-inole) -1H-benzoimidazole-4-carpoxamide (14.1 g) under ice cooling, and the mixture was allowed to stand at room temperature overnight. Stirred. The reaction mixture was concentrated under reduced pressure, and the residue was added with ethyl acetate and diisopropyl ether. The resulting solid was collected by filtration, washed with ethyl acetate and isopropyl ether, and washed with 2-piperidine-4-yl- 1H-Benzimidazole-4-carboxamide ⁇ 2 trifluoroacetate (15.1 g) was obtained.
  • Tables 7 to 9 show the structures of other compounds of the present invention. These can be easily synthesized by using the above-mentioned production methods, the methods described in the examples, and methods obvious to those skilled in the art, or modified methods thereof.
  • the numeral before the substituent indicates the substitution position
  • a numeral having a plurality of numbers indicates a plurality of substitutions.
  • 2-OMe-Ph indicates 2-methoxyphene
  • 2,4-F 2 -Ph indicates 2,4-difluorophenyl.

Abstract

La présente invention concerne un composé pouvant être utilisé dans des traitements destinés à diverses maladies dans lesquelles est impliquée une poly(ADP-ribose) polymérase. Le composé décrit dans cette invention est, soit un dérivé benzimidazole représenté par la formule générale (1), lequel dérivé présente un groupe hétérocyclique substitué à la position 2 et un groupe carbamoyl substitué à la position 4, soit un sel dudit dérivé.
PCT/JP2002/001741 2001-02-28 2002-02-26 Compose benzimidazole WO2002068407A1 (fr)

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WO2003062234A1 (fr) * 2002-01-23 2003-07-31 Yamanouchi Pharmaceutical Co., Ltd. Composes de quinoxaline
WO2004048363A1 (fr) * 2002-11-22 2004-06-10 Takeda Pharmaceutical Company Limited Derives d'imidazole, leur procede de production et d'utilisation
JP2004182730A (ja) * 2002-11-22 2004-07-02 Takeda Chem Ind Ltd イミダゾール誘導体、その製造法及び用途
WO2006110683A1 (fr) * 2005-04-11 2006-10-19 Abbott Laboratories 1h-benzimidazole-4-carboxamides 2-substitues en tant qu'inhibiteurs de parp
US7151102B2 (en) 2000-10-30 2006-12-19 Kudos Pharmaceuticals Limited Phthalazinone derivatives
US7196085B2 (en) 2002-04-30 2007-03-27 Kudos Pharmaceuticals Limited Phthalazinone derivatives
US7449464B2 (en) 2003-03-12 2008-11-11 Kudos Pharmaceuticals Limited Phthalazinone derivatives
US7462724B2 (en) 2005-11-15 2008-12-09 Abbott Laboratories Substituted 1H-benzimidazole-4-carboxamides are potent PARP inhibitors
US7470688B2 (en) 2005-10-19 2008-12-30 Maybridge Limited Phthalazinone derivatives
WO2009029375A1 (fr) * 2007-08-27 2009-03-05 Lead Therapeutics, Inc. Nouveaux inhibiteurs de la poly(adp-ribose)polymérase (parp)
US7550603B2 (en) 2005-04-11 2009-06-23 Abbott Laboratories Inc. 1H-benzimidazole-4-carboxamides substituted with a quaternary carbon at the 2-position are potent PARP inhibitors
US7692006B2 (en) 2006-10-17 2010-04-06 Kudos Pharmaceuticals Limited Phthalazinone derivatives
US7745623B2 (en) 2004-05-21 2010-06-29 Takeda Pharmaceutical Company Limited Cyclic amide derivative, and its production and use
EP2305221A1 (fr) 2003-12-01 2011-04-06 Kudos Pharmaceuticals Limited Inhibiteurs de réparation d'ADN endommagé pour le traitement du cancer
WO2011058367A2 (fr) 2009-11-13 2011-05-19 Astrazeneca Ab Test de diagnostic pour prédire la sensibilité à un traitement par un inhibiteur de poly(adp-ribose) polymérase
EP2336120A1 (fr) 2007-01-10 2011-06-22 Istituto di ricerche di Biologia Molecolare P. Angeletti S.R.L. Combinaisons contenant indazoles à substitution amide utilisés comme inhibiteurs de la poly(ADP-ribose)polymérase (PARP)
US7981890B2 (en) 2007-09-14 2011-07-19 Astrazeneca Ab Phthalazinone derivatives
JP2011521214A (ja) * 2008-05-16 2011-07-21 セルゾーム アーゲー Ｐａｒｐ相互作用分子の同定およびｐａｒｐタンパク質の精製のための方法
US7999117B2 (en) 2006-05-02 2011-08-16 Abbott Lab Substituted 1H-benzimidazole-4-carboxamides are potent PARP inhibitors
US8067613B2 (en) 2007-07-16 2011-11-29 Abbott Laboratories Benzimidazole poly(ADP ribose)polymerase inhibitors
US8093396B2 (en) 2009-01-19 2012-01-10 Abbott Laboratories Benzthiazole inhibitors of poly(ADP-ribose)polymerase
US8129380B2 (en) 2008-01-23 2012-03-06 Astrazeneca Ab Phthalazinone derivatives
JP2012532908A (ja) * 2009-07-14 2012-12-20 ネルビアーノ・メデイカル・サイエンシーズ・エツセ・エルレ・エルレ 選択的ｐａｒｐ−１阻害を有する３−オキソ−２，３−ジヒドロ−１ｈ−イソインドール−４−カルボキサミド
JP2012532907A (ja) * 2009-07-14 2012-12-20 ネルビアーノ・メデイカル・サイエンシーズ・エツセ・エルレ・エルレ Ｐａｒｐ阻害剤としての３−オキソ−２，３−ジヒドロ−１ｈ−イソインドール−４−カルボキサミド
US8436185B2 (en) 2008-01-08 2013-05-07 Merck Sharp & Dohme Corp. Pharmaceutically acceptable salts of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
US8475842B2 (en) 2008-10-07 2013-07-02 Astrazeneca Ab Immediate release pharmaceutical formulation of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one
US8912187B2 (en) 2003-03-12 2014-12-16 Kudos Pharmaceuticals Limited Phthalazinone derivatives
CN104860919A (zh) * 2015-03-26 2015-08-26 天津药物研究院有限公司 含哌啶的苯并咪唑衍生物及其制备方法和用途
WO2018162439A1 (fr) 2017-03-08 2018-09-13 Onxeo Nouveau biomarqueur prédictif de la sensibilité à un traitement du cancer avec une molécule dbait
WO2018197461A1 (fr) 2017-04-28 2018-11-01 Akribes Biomedical Gmbh Inhibiteur de parp en combinaison avec un glucocorticoïde et/ou l'acide ascorbique et/ou un facteur de croissance de protéine pour le traitement d'une mauvaise cicatrisation de plaie
CN109232540A (zh) * 2018-06-15 2019-01-18 深圳市坤健创新药物研究院 一种取代苯并咪唑衍生物及应用
WO2019175132A1 (fr) 2018-03-13 2019-09-19 Onxeo Molécule dbait contre la résistance acquise dans le traitement du cancer
EP3594343A1 (fr) 2015-07-23 2020-01-15 Institut Curie Utilisation d'une combinaison d'une molecule dbait et d'inhibiteurs de parp pour le traitement du cancer
US10799501B2 (en) 2015-11-05 2020-10-13 King's College Hospital Nhs Foundation Trust Combination of an inhibitor of PARP with an inhibitor of GSK-3 or DOT1L
WO2021048235A1 (fr) 2019-09-10 2021-03-18 The Francis Crick Institute Limited Traitement du cancer à déficit de hr
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation

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US7151102B2 (en) 2000-10-30 2006-12-19 Kudos Pharmaceuticals Limited Phthalazinone derivatives
WO2003062234A1 (fr) * 2002-01-23 2003-07-31 Yamanouchi Pharmaceutical Co., Ltd. Composes de quinoxaline
US7196085B2 (en) 2002-04-30 2007-03-27 Kudos Pharmaceuticals Limited Phthalazinone derivatives
WO2004048363A1 (fr) * 2002-11-22 2004-06-10 Takeda Pharmaceutical Company Limited Derives d'imidazole, leur procede de production et d'utilisation
JP2004182730A (ja) * 2002-11-22 2004-07-02 Takeda Chem Ind Ltd イミダゾール誘導体、その製造法及び用途
US7449464B2 (en) 2003-03-12 2008-11-11 Kudos Pharmaceuticals Limited Phthalazinone derivatives
US9566276B2 (en) 2003-03-12 2017-02-14 Kudos Pharmaceuticals Limited Phthalazinone derivatives
US11160803B2 (en) 2003-03-12 2021-11-02 Kudos Pharmaceuticals Limited Phthalazinone derivatives
US9169235B2 (en) 2003-03-12 2015-10-27 Kudos Pharmaceuticals Limited Phthalazinone derivatives
US10449192B2 (en) 2003-03-12 2019-10-22 Kudo Pharmaceuticals Limited Phthalazinone derivatives
US8912187B2 (en) 2003-03-12 2014-12-16 Kudos Pharmaceuticals Limited Phthalazinone derivatives
US7662818B2 (en) 2003-03-12 2010-02-16 Kudos Pharmaceuticals Limited Phthalazinone derivatives
EP2305221A1 (fr) 2003-12-01 2011-04-06 Kudos Pharmaceuticals Limited Inhibiteurs de réparation d'ADN endommagé pour le traitement du cancer
US7745623B2 (en) 2004-05-21 2010-06-29 Takeda Pharmaceutical Company Limited Cyclic amide derivative, and its production and use
US8697865B2 (en) 2004-05-21 2014-04-15 Takeda Pharmaceutical Company Limited Cyclic amide derivative, and its production and use
US7728026B2 (en) 2005-04-11 2010-06-01 Abbott Laboratories, Inc. 2-substituted-1 h-benzimidazile-4-carboxamides are PARP inhibitors
US8217070B2 (en) 2005-04-11 2012-07-10 Abbott Laboratories 2-substituted-1H-benzimidazole-4-carboxamides are PARP inhibitors
US7550603B2 (en) 2005-04-11 2009-06-23 Abbott Laboratories Inc. 1H-benzimidazole-4-carboxamides substituted with a quaternary carbon at the 2-position are potent PARP inhibitors
WO2006110683A1 (fr) * 2005-04-11 2006-10-19 Abbott Laboratories 1h-benzimidazole-4-carboxamides 2-substitues en tant qu'inhibiteurs de parp
US7902193B2 (en) 2005-10-19 2011-03-08 Maybridge Limited Phthalazinone derivatives
US7470688B2 (en) 2005-10-19 2008-12-30 Maybridge Limited Phthalazinone derivatives
US7595406B2 (en) 2005-11-15 2009-09-29 Abbott Laboratories Inc. Substituted 1H-benzimidazole-4-carboxamides are potent PARP inhibitors
US7462724B2 (en) 2005-11-15 2008-12-09 Abbott Laboratories Substituted 1H-benzimidazole-4-carboxamides are potent PARP inhibitors
US7999117B2 (en) 2006-05-02 2011-08-16 Abbott Lab Substituted 1H-benzimidazole-4-carboxamides are potent PARP inhibitors
US7692006B2 (en) 2006-10-17 2010-04-06 Kudos Pharmaceuticals Limited Phthalazinone derivatives
US8071623B2 (en) 2007-01-10 2011-12-06 Instituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Amide substituted indazoles as poly(ADP-ribose)polymerase(PARP) inhibitors
EP2336120A1 (fr) 2007-01-10 2011-06-22 Istituto di ricerche di Biologia Molecolare P. Angeletti S.R.L. Combinaisons contenant indazoles à substitution amide utilisés comme inhibiteurs de la poly(ADP-ribose)polymérase (PARP)
EP2805945A1 (fr) 2007-01-10 2014-11-26 MSD Italia S.r.l. Indazoles substitués d'amide en tant qu'inhibiteurs PARP de poly(ADP-ribose)polymérase
US8067613B2 (en) 2007-07-16 2011-11-29 Abbott Laboratories Benzimidazole poly(ADP ribose)polymerase inhibitors
WO2009029375A1 (fr) * 2007-08-27 2009-03-05 Lead Therapeutics, Inc. Nouveaux inhibiteurs de la poly(adp-ribose)polymérase (parp)
US7981890B2 (en) 2007-09-14 2011-07-19 Astrazeneca Ab Phthalazinone derivatives
US8436185B2 (en) 2008-01-08 2013-05-07 Merck Sharp & Dohme Corp. Pharmaceutically acceptable salts of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
US8129380B2 (en) 2008-01-23 2012-03-06 Astrazeneca Ab Phthalazinone derivatives
JP2011521214A (ja) * 2008-05-16 2011-07-21 セルゾーム アーゲー Ｐａｒｐ相互作用分子の同定およびｐａｒｐタンパク質の精製のための方法
US8475842B2 (en) 2008-10-07 2013-07-02 Astrazeneca Ab Immediate release pharmaceutical formulation of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one
US11975001B2 (en) 2008-10-07 2024-05-07 Kudos Pharmaceuticals Limited Immediate release pharmaceutical formulation of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one
US11633396B2 (en) 2008-10-07 2023-04-25 Kudos Pharmaceuticals Limited Immediate release pharmaceutical formulation of 4-[3-(4- cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H- phthalazin-1-one
US8093396B2 (en) 2009-01-19 2012-01-10 Abbott Laboratories Benzthiazole inhibitors of poly(ADP-ribose)polymerase
JP2012532907A (ja) * 2009-07-14 2012-12-20 ネルビアーノ・メデイカル・サイエンシーズ・エツセ・エルレ・エルレ Ｐａｒｐ阻害剤としての３−オキソ−２，３−ジヒドロ−１ｈ−イソインドール−４−カルボキサミド
JP2012532908A (ja) * 2009-07-14 2012-12-20 ネルビアーノ・メデイカル・サイエンシーズ・エツセ・エルレ・エルレ 選択的ｐａｒｐ−１阻害を有する３−オキソ−２，３−ジヒドロ−１ｈ−イソインドール−４−カルボキサミド
WO2011058367A2 (fr) 2009-11-13 2011-05-19 Astrazeneca Ab Test de diagnostic pour prédire la sensibilité à un traitement par un inhibiteur de poly(adp-ribose) polymérase
CN104860919A (zh) * 2015-03-26 2015-08-26 天津药物研究院有限公司 含哌啶的苯并咪唑衍生物及其制备方法和用途
EP3594343A1 (fr) 2015-07-23 2020-01-15 Institut Curie Utilisation d'une combinaison d'une molecule dbait et d'inhibiteurs de parp pour le traitement du cancer
US10799501B2 (en) 2015-11-05 2020-10-13 King's College Hospital Nhs Foundation Trust Combination of an inhibitor of PARP with an inhibitor of GSK-3 or DOT1L
WO2018162439A1 (fr) 2017-03-08 2018-09-13 Onxeo Nouveau biomarqueur prédictif de la sensibilité à un traitement du cancer avec une molécule dbait
WO2018197461A1 (fr) 2017-04-28 2018-11-01 Akribes Biomedical Gmbh Inhibiteur de parp en combinaison avec un glucocorticoïde et/ou l'acide ascorbique et/ou un facteur de croissance de protéine pour le traitement d'une mauvaise cicatrisation de plaie
WO2019175132A1 (fr) 2018-03-13 2019-09-19 Onxeo Molécule dbait contre la résistance acquise dans le traitement du cancer
CN109232540A (zh) * 2018-06-15 2019-01-18 深圳市坤健创新药物研究院 一种取代苯并咪唑衍生物及应用
WO2021048235A1 (fr) 2019-09-10 2021-03-18 The Francis Crick Institute Limited Traitement du cancer à déficit de hr
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation

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